This invention relates to compositions comprising a salt of an arylpiperazinyl-C2 or -C4 alkyleneheterocycle and a cyclodextrin.
Formulation of pharmaceutical dosage forms is frequently hampered by poor aqueous solubility and/or stability of the drug of interest, which in turn can severely limit its therapeutic application. Conversely, increasing drug solubility and stability through appropriate formulation can accordingly lead to increased therapeutic efficacy of the drug. Various methods have been used to increase the solubility and stability of drugs such as the use of organic solvents, emulsions, liposomes and micelles, adjustments to pH and the dielectric constant of formulations solvent systems, chemical modifications, and complexation of the drugs with appropriate complexing agents such as cyclodextrins.
Cyclodextrins, sometimes referred to as Schardinger""s dextrins, were first isolated by Villiers in 1891 as a digest of Bacillus amylobacter on potato starch. The foundations of cyclodextrin chemistry were laid down by Schardinger in the period 1903-1911. Until 1970, however, only small amounts of cyclodextrins could be produced in the laboratory and the high production cost prevented the usage of cyclodextrins in industry. In recent years, dramatic improvements in cyclodextrin production and purification have been achieved and cyclodextrins have become much less expensive, thereby making the industrial application of cydodextrins possible.
Cyclodextrins are cyclic oligosaccharides with hydroxyl groups on the outer surface and a void cavity in the center. Their outer surface is hydrophilic, and therefore they are usually soluble in water, but the cavity has a lipophilic character. The most common cyclodextrins are xcex1-cyclodextrin, xcex2-cyclodextrin and xcex3-cyclodextrin, consisting of 6; 7 and 8 xcex1-1,4-linked glucose units, respectively. The number of these units determines the size of the cavity.
Cyclodextrins are capable of forming inclusion complexes with a wide variety of hydrophobic molecules by taking up a whole molecule (a xe2x80x9cguest moleculexe2x80x9d), or some part of it, into the void cavity. The stability of the resulting complex depends on how well the guest molecule fits into the cyclodextrin cavity. Common cyclodextrin derivatives are formed by alkylation (e.g., methyl-and-ethyl-xcex2-cydodextrin) or hydroxyalkylation of the hydroxyethyl-derivatives of xcex1-, xcex2-, and xcex3-cyclodextrin) or by substituting the primary hydroxyl groups with saccharides (e.g., glucosyl- and maltosyl- xcex2-cyclodextrin). Hydroxypropyl-xcex2-cyclodextrin and its preparation by propylene oxide addition to xcex2-cyclodextrin, and hydroxyethyl-xcex2-cyclodextrin and its preparation by ethylene oxide addition to xcex2-cyclodextrin, were described in a patent of Gramera et al. (U.S. Pat. No. 3,459,731, issued August 1969) over 20 years ago.
Although cyclodextrins have been used to increase the solubility, dissolution rate and/or stability of a great many compounds, it is also known there are many drugs for which cyclodextrin complexation either is not possible or yields no advantages. See J. Szejtli, Cyclodextrins in Drug Formulations: Part II, Pharmaceutical Technology, 24-38, August, 1991.
It is conventionally believed that a salt of a drug dissolves in a cyclodextrin-containing aqueous medium by simply dissociating to form a charged drug molecule and a counter-ion, and that it is the dissociated (charged) drug molecule which acts as a guest moiety and forms inclusion complexes with the cyclodextrin. A consequence of this is the belief that there are no differences in equilibrium solubility among the salts of a given drug in a specific cyclodextrin. Thus, if a solubility-phase diagram is generated for a particular drug in a particular aqueous cyclodextrin (i.e., a plot of the equilibrium solubility of a drug salt in the aqueous cyclodextrin as a function of cyclodextrin concentration), different salts of the drug should plot out as lines having the same slope.
The present invention is based, inter alia, on the determination that the solubility of the compounds presented below form stable inclusion complexes with cyclodextrins, and that such inclusion complexes are highly water soluble relative to the non-complexed drug.
The present invention is further based on the unexpected and surprising discovery that, in a particular cyclodextrin, there are solubility differences among particular salts of the aryl-heterocyclics useful herein. A particular salt of a specific aryl-heterocyclic can exhibit much greater solubility in a particular aqueous cycdodextrin solution than a different salt of the same aryleterocycle in the same cyclodextrin. Some salts show unexpectedly high solubility. Many, if not all, of the salts investigated for this invention exhibited their own distinctive slope when plotted on a solubility-phase diagram.
In the particular case of the aryl-heterocyclic ziprasidone, it has been determined that the order of solubility (e.g., the increasing order of solubility) of a series of different ziprasidone salts in aqueous cyclodextrin solution does not necessarily correlate with the order of solubility of those same salts in water.
In one embodiment this invention provides compositions of matter comprising a cyclodextrin and a pharmaceutically acceptable salt of a compound (herein referred to as an xe2x80x9caryl-heterocyclicxe2x80x9d) having the formula 
wherein
Ar is benzoisothiazolyl or an oxide or dioxide thereof each optionally substituted by one fluoro, chloro, trifluoromethyl, methoxy, cyano, or nitro;
n is 1 or 2; and
X and Y together with the phenyl to which they are attached form benzothiazolyl; 2-aminobenzothiazolyl; benzoisothiazolyl; indazolyl; 3-hydroxyindazolyl; indolyl; oxindolyl optionally substituted by one to three of (C1-C3)alkyl, or one of chloro, fluoro or phenyl, said phenyl optionally substituted by one chloro or fluoro; benzoxazolyl; 2-aminobenzoxazolyl; benzoxazolonyl; 2-aminobenzoxazolinyl; benzothiazolonyl; benzoimidazolonyl; or benzotriazolyl. The preceding compounds are disclosed in U.S. Pat. No. 4,831,031, herein incorporated by reference in its entirety.
A preferred subgroup of the above compositions is the subgroup wherein X and Y together with the phenyl to which they are attached form oxindole; A preferred subgroup within this subgroup occurs when the oxindole moiety is 6-chlorooxindole-5-yl.
A further preferred subgroup of compositions is the subgroup wherein Ar is benzoisothiazolyl.
A further preferred subgroup of compositions is the subgroup wherein n is 1.
A preferred aryl-heterocyclic is ziprasidone, which has the structure 
It is also disclosed in the previously mentioned U.S. Pat. No. 4,831,031, has utility as a neuroleptic, and is thus useful as an antipsychotic.
Further preferred compositions of matter comprise a pharmaceutically acceptable salt of ziprasidone and a cyclodextrin,
wherein said salt is selected from the tosylate, tartrate, napsylate, besylate, aspartate, esylate and mesylate salt;
and wherein said cyclodextrin is selected from xcex3-cyclodextrin, SBECD and HPBCD.
This invention thus provides compositions of matter comprising a pharmaceutically acceptable salt of an aryl-heterocyclic and a cyclodextrin. The compositions can be administered orally, for example as a tablet or capsule, or parenterally, for example, as an injectable or by inhalation to a mammal in need thereof,
The phrase xe2x80x9ccomposition(s) of matterxe2x80x9d as used herein including the appendant claims encompasses, inter alia, compositions of an aryl-heterocyclic and a cyclodextrin which are dry physical mixtures, which are dry inclusion complexes, and which are aqueous solutions of dissolved inclusion complexes. For example, a composition can comprise a dry mixture of an aryl-heterocyclic physically mixed with a dry cydodextrin. A composition, in a preferred embodiment, can also comprise an aqueous solution which has been lyophilized or otherwise dried (e.g., in a vacuum oven or other suitable device), such that the composition comprises a dry, pre-formed inclusion complex of cyclodextrin-complexed aryl-heterocyclic which can later be re-constituted. A composition can also comprise the aqueous solution itself, i.e., an aryl-heterocyclic plus cyclodextrin plus water. Inclusion complexes are thus within the scope of the term xe2x80x9ccomposition of matterxe2x80x9d whether they are preformed, formed in situ, or formed in vivo.
The aryl-heterocyclic salt is advantageously relatively highly soluble in aqueous cyclodextrin solution, and if administered to a patient parenterally as an aqueous solution, can accordingly be administered in a relatively small injection volume.
Physical mixtures of a cyclodextrin and an aryl-heterocyclic are usefully employed and are within the scope of this invention. A mixture of a cyclodextrin and an aryl-heterocyclic, for example used as fill for a capsule or compressed into a tablet for oral administration, will form an inclusion complex on exposure to an aqueous environment of use such as the luminal fluid of the gastrointestinal tract or the salivary fluid of the buccal cavity, and thereby aid in increasing bioavailability relative to the uncomplexed drug. Cyclodextrin can be present in an amount over that needed to complex the drug completely since extra cyclodextrin aids in dissolution of the dosage form once it contacts aqueous fluid.
In a further aspect, this invention provides compositions of matter suitable for administration to a human patient as a solution (e.g., as an injectable or intranasally), comprising an inclusion complex of a salt of ziprasidone in a cyclodextrin. Advantageously, in a preferred embodiment said inclusion complex provides an amount of ziprasidone of at least 2.5 mgA/ml when the amount of ziprasidone (or other aryl-heterocyclic) provided by said complex is measured at a cyclodextrin concentration of 40% w/v in water.
Inclusion complexes that provide at least 10 mgA/ml of ziprasidone at 40% w/v in water are more preferred.
Inclusion complexes that provide at least 15 mgA/ml of ziprasidone at 40% w/v are most preferred.
As a further feature of the invention, the mesylate, esylate, and tartrate salts of ziprasidone are provided.
The phrase xe2x80x9cmgAxe2x80x9d indicates the weight (in mg) of ziprasidone (or other aryl-heterocyclic) calculated as the free base, (for ziprasidone, molecular weight=412.9).
The phrase xe2x80x9cmeasured at a cyclodextrin concentration of 40% w/v in waterxe2x80x9d as used above and in the claims provides a standard against which the degree of solubility of a particular inclusion complex of ziprasidone in a particular cyclodextrin, and hence its usefulness, can be compared. The phrase is not to be interpreted as limiting the invention in any way. For example, assume that a test solution of a particular cyclodextrin X in water is made up to 40% w/v (xe2x80x9cw/vxe2x80x9d being based, of course, on the weight xe2x80x9cwxe2x80x9d of the cyclodextrin in water, xe2x80x9cvxe2x80x9d referring to the total solution volume), and that this test solution, at equilibrium solubility, provides a concentration of 10 mgA/ml of ziprasidone salt Y. The (dry or non-solvated) inclusion complex (i.e., of ziprasidone salt Y in cyclodextrin X) used to make the 40% test solution thus represents a preferred inclusion complex because it exceeds the standard of 2.5 mgA/ml. Assuming that the solubility phase diagram for ziprasidone salt X is linear and passes through the origin, an inclusion complex of salt Y in the same cyclodextrin X, for example at an aqueous cyclodextrin concentration of 20% w/v, will provide 5 mgA/ml. The inclusion complex used to make this second solution is equally preferred even though a different concentration of cyclodextrin in water was employed to make the ziprasidone salt solubility measurement.
Viewed alternatively, an aqueous cyclodextrin test concentration of 40% w/v provides a point at which a determination can be made regarding whether a cyclodextrin inclusion complex of a particular ziprasidone salt in a particular cyclodextrin can provide at least 2.5 mgA/ml of ziprasidone. If such determination is positive, any inclusion complex made with that salt and that cyclodextrin is preferred.
Use of the term xe2x80x9csaltxe2x80x9d herein, including the appendant claims, shall be understood to refer to pharmaceutically acceptable acid addition salts of aryl-heterocyclics, including ziprasidone. The salts employed can be anhydrous or in the form of one or more solvates, such as hydrates, including mixtures thereof. The salts may occur in different polymorphic forms. For example, co-pending U.S. provisional application 60/1016537, herein incorporated by reference, discloses the mesylate trihydrate salt of ziprasidone. Co-pending U.S. provisional application 60/016757, herein incorporated by reference, discloses the mesylate dihydrate salt of ziprasidone.
xe2x80x9cProduct solutionxe2x80x9d as used herein, including the appendant claims, means an aqueous solution of a salt of an aryl-heterocyclic (including ziprasidone) inclusion complex in a cyclodextrin, which solution is pharmaceutically acceptable and ready for administration to a patient.
The fact that different aryl-heterocyclic salts can exhibit differing solubilities in a particular aqueous cyclodextrin solution is applicable to cyclodextrins in general, including those which are presently known. Useful cyclodextrins include xcex1, xcex2, and xcex3 cyclodextrins, methylated cyclodextrins, hydroxypropyl-xcex2-cyclodextrin (HPBCD), hydroxyethyl-xcex2-cyclodextrin (HEBCD), branched cyclodextrins in which one or two glucoses or maltoses are enzymatically attached to the cyclodextrin ring, ethyl- and ethyl-carboxymethyl cyclodextrins, dihydroxypropyl cyclodextrins, and sulfoalkyl ether cyclodextrins. The degree of substitution is not considered to be critical, and the cyclodextrins just mentioned can have essentially any degree of substitution (per entire cyclodextrin molecule) as known in the art. Mixtures of cyclodextrins, as well as single species, are feasible for making dosage forms according to the invention.
xcex2-cyclodextrin sulfobutyl ether (SBECD), hydroxypropyl xcex2-cyclodextrin (HPBCD), and xcex3-cyclodextrin are preferred for use in this invention. HPBCD and SBECD are preferred for parenteral administration. For oral administration xcex3-cyclodextrin is preferred. HPBCD is well known in the art, see for example Publication R 81 216 entitled xe2x80x9cEncapsin HPBxe2x80x9d from Janssen Biotech N.V. SBECD is also known and has been disclosed in U.S. Pat. Nos. 5,376,645 and 5,134,127, both to Stella et al. and both herein incorporated by reference in their entirety.
A preferred group of inclusion complexes of ziprasidone salts includes
(1) the tosylate, napsylate, besylate, aspartate, tartrate, esylate (ethanesulfonate) ormesylate (methanesulfonate) salts of ziprasidone, each complexed with SBECD; and
(2) the tartrate, esylate, or mesylate salts of ziprasidone, each complexed with HPBCD.
A more preferred group of inclusion complexes of ziprasidone salts includes
(1) the tosylate, napsylate, besylate, tartrate, esylate or mesylate salts of ziprasidone, each complexed with SBECD; and
(2) the tartrate, esylate, or mesylate salts of ziprasidone, each complexed with HPBCD.
A still more preferred group of inclusion complexes of ziprasidone salts includes
(1) the tartrate, esylate, or mesylate salts of ziprasidone, each complexed with SBECD; and
(2) the tartrate, esylate or mesylate salts of ziprasidone, each complexed with HPBCD.
A still more preferred group of inclusion complexes of ziprasidone salts include ziprasidone mesylate or tartrate, each complexed with SBECD.
Most preferred is ziprasidone mesylate complexed with SBECD.
The inclusion complexes of this invention can be administered orally and parenterally, as previously noted.
As previously noted, this invention is based, inter alia, on the determination that, for a particular cyclodextrin, the solubility of an aryl-heterocyclic salt such as a ziprasidone salt in that cyclodextrin is dependent on the particular salt employed. That is, different aryl-heterocyclic salts, including ziprasidone, exhibit (sometimes widely) differing solubilities in the same cyclodextrin. This phenomenon of variable solubility is particularly important for parenteral administration because it allows for increasing the loading of an aryl-heterocydic in a cyclodextrin by selecting a salt with relatively high cyclodextrin solubility. Increased loading in turn allows for the capability of parenterally delivering a given dose of aryl-heterocyclic in a relatively decreased injection volume. Viewed alternatively, since the weight of cyclodextrin required to dissolve a given weight of an aryl-heterocyclic decreases with increasing salt solubility in an aqueous solution of the cyclodextrin, and assuming a constant loading of ziprasidone, injection volume can be reduced by choosing an appropriate, highly soluble salt. It is well known in the medical arts that pain on injection can increase in proportion to the injection volume employed. Patient compliance with parenteral administration can be affected accordingly. Thus the ability to administer ziprasidone in a decreased injection volume represents a significant advance in this art. For example, in many cases, this invention provides therapeutic solutions of a ziprasidone inclusion complex which provide the maximum once-daily level of ziprasidone in a single injection volume less than 2 ml.